1. Field of the Invention
The invention relates to immunotherapy. More specifically the invention relates to the use of a patient-derived cell/non-patient cell hybrid as a therapeutic vaccine. Most specifically the invention relates to a novel cell line, FO-1 #12, for use in generating a therapeutic vaccine for cancer and Acquired Immunodeficiency Syndrome (AIDS).
2. Background Art
For years cancer has evaded immunotherapeutic treatment. The last few years have registered a dramatic expansion in the understanding of tumor immunology, thanks to a series of major discoveries ranging from the identification and molecular characterization of tumor rejection antigens (1-4), to the discovery of co-stimulating molecules like B7 which are expressed on the surface of antigen-presenting cells and are crucial to the effectiveness of the immune activation associated with presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules (5,6). However, these discoveries have not led to any significant breakthrough in cancer treatment. Taken together the results of these studies point out a major difficulty in tumor immunotherapy; that antigenicity (i.e., the ability to express a tumor antigen) and immunogenicity (i.e., the ability to induce an effective immune response) are not synonyms. In fact, an increasing body of experimental evidence indicates that tumor antigens are present even in poorly or non-immunogenic tumors. A clearer understanding of these difficulties has led to efforts aimed at greatly amplifying the immunogenicity of tumor cells, by engineering them to express specific molecules (5-7). However, these efforts have met with only limited success, because they are technically complicated and, therefore, of limited use for treating human cancer.
The inability to mount an effective response against spontaneous tumors has also been ascribed to alterations in the immune capacity of the tumor-bearing host. Establishment of immunotolerance in cancer patients may prevent effective immunization (8); in fact, several tumors have been shown to produce IL-10 (9), a cytokine that inhibits the production of a variety of immunoaugmenting cytokines (10,11). This situation further complicates the prospects for immunotherapy.
Jami and Ritz (12) first described the immunization of inbred mice with somatic cell hybrids derived from the fusion of syngeneic tumor cells with allogeneic cells. Specifically, they showed that inbred 129/Sv mice were resistant to the inoculation of a tumorigenic challenge with syngeneic teratocarcinoma cells following pre-immunization with (teratocarcinoma X C3H L-cell) semi-allogeneic somatic cell hybrids. Similar observations were reported by Parkman (13) with tumor cell hybrids obtained by the fusion of EL-4 lymphoma cells (H-2.sup.b) with C3H fibroblasts (H-2.sup.k). These hybrids specifically immunized C57BL/6 (H-2.sup.b) mice against a lethal challenge with EL-4 lymphoma cells. Several subsequent studies also described this immunotherapeutic approach (14-17). These later studies also showed that the adoptive transfer of immunity induced by semiallogeneic cells required T lymphocytes; that the enhanced immunity was not due to an allogeneic effect, but was probably the result of an association of tumor-associated antigens (TAA) with allogeneic molecules; and that the TAA and the alloantigen needed to be on the same cell (the hybrid).
It also has been shown that immunization of experimental primates with allogeneic or xenogeneic (human) lymphocytes protects these animals against a challenge with simian immunodeficiency virus (SIV) grown in allogeneic (simian) or xenogeneic (human) cells (18,19). Since SIV is the simian equivalent of human immunodeficiency virus (HIV), the causative agent of AIDS in humans, these findings have major implications for AIDS vaccine development.
However, in spite of major advances in our understanding of immunology, immunotherapy does not yet represent a routine modality for treatment of cancer or AIDS. Moreover, current immunotherapeutic regimens tend to be cumbersome, labor-intensive, expensive, and only apply to a very limited number of cancer types (mostly melanoma and renal cell carcinoma).
Furthermore, despite the fact that semi-allogeneic tumor cell hybrids were used to immunize experimental animals as long ago as 1973 (12), there have been no successes using semi-allogeneic hybrids to treat human cancer. Similarly, there have been no successes using semi-allogeneic hybrids to treat AIDS. Furthermore, no semi-allogenic tumor cell hybrid exists that can be used to treat human cancer or AIDS.
Thus, this invention provides a novel type of therapeutic vaccine based on patient-specific, irradiated semiallogeneic cell hybrids, that could be used to treat any type of cancer as well as AIDS. The use of the present semiallogeneic cell hybrids is technically straight-forward, and entails modest expense compared to most cancer treatment regimens.